Recently we performed a comprehensive analysis of interferon (IFN)-gamma gene polymorphisms for association with IFN-alfa induced and spontaneous recovery from hepatitis C virus (HCV) infection. We genotyped eight single nucleotide polymorphisms (SNPs) spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronic HCV-infected patients who had received IFN-alfa based therapy and the second was 251 intravenous drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region, -764G, was significantly associated with sustained virological response (SVR) P0.01, OR2.7 (1.3-5.6). The association was independently significant in multiple logistic regression (P 0.04) along with race, viral titer and genotype. This variant was also significantly associated with spontaneous recovery P0.04, OR3.51(1.0-12.5) in the second cohort. In the promoter assay, the -764G IFN-gamma promoter variant had a two- to three-fold higher activity than the common -764C. Electrophoretic mobility shift assay demonstrated that this SNP is located in a specific binding site of a yet-unidentified nuclear factor and the binding affinity was significantly higher with the G than the C allele. Our study suggests that the SNP at position -764 of the IFN-gamma promoter is functionally important in determining viral clearance and treatment response and may be used as a genetic marker to predict SVR in HCV-infected patients. [unreadable] [unreadable] We also evaluated other candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-1 (TGF-b), interleukin-10 (IL-10) and interferon-gamma (IFNG), for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic hepatitis C virus (HCV) infection (194 Caucasian Americans (CAs) and 180 African Americans (AAs)), using a genetic haplotype approach. Among the 14 haplotypes that occurred with a frequency 10% in the cohort overall, the Mx1-(-123C)-(6886A)-(19820G(379V))-(38645T) (abbreviated Mx1-CAGT), and PKR-(110T)-(7949G)-(13846A)-(22937T)-(40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak 3 vs <3). These associations persisted after adjustment for potential confounders such as alcohol use, gender, age (which is strongly correlated with the estimated duration of HCV infection (Spearmans correlation coefficient (rs)0.6)), and race (for Mx1-CAGT: OR0.33; 95%C.I.: 0.16-0.68; P0.0027; and for PKR-TGATT: OR0.56; 95%C.I.:0.32-0.98; P0.0405). Population structure was evaluated using the structured association method using data from 161 ancestry-informative markers and did not affect our findings. We utilized an independent cohort of 34 AA and 160 CA to validate our findings. We did not observe similar associations for these haplotypes and fibrosis in the validation set, although there were notable differences in the characteristics of both patients groups.